Rheumatoid arthritis is a chronic arthropathy characterized by inflammation, proliferation and destruction of the articular cartilage. Although historically cartilage has been considered to be an "innocent bystander" of the disease, recent evidence suggests that the degradation of cartilage in arthritis involves an imbalance of the anabolic and catabolic activities of the articular chondrocytes, secondary to synovitis and joint inflammation. Chondrocyte metabolic activity is strongly influenced by soluble mediators (e.g., cytokines) and biophysical factors (e.g., mechanical stress). In particular, biomechanical factors may play an important role in the onset and progression of degenerative arthritis secondary to joint inflammation in rheumatoid arthritis. However, the sequence of biomechanical and biochemical processes regulating these events in vivo is still unclear. The primary hypothesis of this study is that, in rheumatoid arthritis, a loss of cartilage biomechanical function and the presence of inflammatory cytokines alters the metabolic response of chondrocytes to mechanical stress. Aim 1 of this project is to measure the mechanical properties of the cartilage extracellular and pericellular matrices in RA, and to incorporate this data in a theoretical model of the micromechanical environment of the cell. In Aim 2, we will determine the role of stress magnitude in the stimulation of nitric oxide and prostaglandin E2 production by chondrocytes, and determine the influence of these inflammatory mediators on matrix turnover. In Aim 3, we will determine whether mechanical stress has an additive or antagonistic effect on with certain inflammatory cytokines (interleukin 1, tumor necrosis factor alpha, and interleukin 17) in controlling the PGE2 synthesis and matrix metabolism. Currently, there is little information on the biomechanical changes in articular cartilage with RA. Understanding the biomechanical and molecular mechanisms of chondrocyte response to physiologic loading in an inflammatory environment may enable new therapies that are specific to the stage of the disease. As many pharmacologic therapies for RA are focusing on the NOS2 and COX2 pathways, investigation of the interaction of physical therapies with these pathways will hopefully lead to more safe and effective treatments for RA.